title: Amelioration of muscular dystrophy by transgenic expression of Niemann-Pick C1.
abstract: Duchenne muscular dystrophy (DMD) and other types of muscular dystrophies are caused by the loss or alteration of different members of the dystrophin protein complex. Understanding the molecular mechanisms by which dystrophin-associated protein abnormalities contribute to the onset of muscular dystrophy may identify new therapeutic approaches to these human disorders. By examining gene expression alterations in mouse skeletal muscle lacking alpha-dystrobrevin (Dtna(-/-)), we identified a highly significant reduction of the cholesterol trafficking protein, Niemann-Pick C1 (NPC1). Mutations in NPC1 cause a progressive neurodegenerative, lysosomal storage disorder. Transgenic expression of NPC1 in skeletal muscle ameliorates muscular dystrophy in the Dtna(-/-) mouse (which has a relatively mild dystrophic phenotype) and in the mdx mouse, a model for DMD. These results identify a new compensatory gene for muscular dystrophy and reveal a potential new therapeutic target for DMD.
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Steen
authors.forename: Marvin E
authors.initials: ME
authors.lastname: Adams
authors.forename: Yan
authors.initials: Y
authors.lastname: Tesch
authors.forename: Stanley C
authors.initials: SC
authors.lastname: Froehner
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism; D049029:Dystrophin-Associated Proteins / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000166:cytology / Q000473:pathology / Q000502:physiology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism; D000077296:Niemann-Pick C1 Protein; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D019076:Transgenes
chemical_list: D016189:Dystrophin; D049029:Dystrophin-Associated Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; C098885:dystrobrevin